Novel dihydropyridine compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions can be treated with therapeutic agents that open potassium channels; see (K. Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (D. R. Gehlert et al., Prog. Neuro-Psychopharmacol and Biol. Psychiat., v. 18, pp. 1093-1102 (1994)); (M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993)); (J. E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996)); (D. E. Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (B. B. Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995)); and (D. Spanswick et al., Nature, v. 390 pp. 521-25 (Dec. 4, 1997)). Such diseases or conditions include asthma, epilepsy, male sexual dysfunction, female sexual dysfunction, migraine, pain, urinary incontinence, stroke, Raynaud""s Syndrome, eating disorders, functional bowel disorders, and neurodegeneration.
Potassium channel openers also act as smooth muscle relaxants. Because urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle provides a method to ameliorate or prevent urinary incontinence.
Journal of Cardiovascular Pharmacology 8:1168-1175, (1986) Raven Press, New York, EP 0 059 291, EP 87051738, U.S. Pat. No. 4,321,384, U.S. Pat. No. 4,551,534, U.S. Pat. No. 4,596,873, and U.S. Pat. No. 4,618,678 all disclose 4-(aryl)-4,5,6,7,8,-hexahydro-2-alkyl-5-oxo-1,7-naphthyridine-3-carboxylic esters as calcium entry blockers that may be useful as antihypertensive agents.
Compounds of the present Invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions and are useful for treating diseases that can be ameliorated by opening potassium channels.
In its principle embodiment of the present invention, compounds of the present invention have formula I 
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein
n is 0-1;
m is 1-2;
A is selected from the group consisting of NR2, O, and S;
Axe2x80x2 is selected from the group consisting of NR3, O, S, and CR4R5;
D is selected from the group consisting of CH2 and C(O);
Dxe2x80x2 is selected from the group consisting of CH2, C(O), S(O), and S(O)2;
R1 is selected from the group consisting of aryl and heterocycle;
R2 and R3 are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NZ1Z2, and (NZ1Z2)alkyl wherein Z1 and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl;
R4 and R5 are independently selected from the group consisting of hydrogen and alkyl;
or
R4 and R5 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring;
R6 and R7 are independently selected from the group consisting of hydrogen and alkyl;
or
R6 and R7 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring; and
R8 and R9 are independently selected from the group consisting of hydrogen and alkyl;
or
R8 and R9 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring;
with the proviso that when D is CH2 then Dxe2x80x2 is other than CH2; and
with the proviso that when Dxe2x80x2 is S(O) or S(O)2 then Axe2x80x2 is CR4R5.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principle embodiment of the present invention, compounds of the present invention have formula I 
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein
n is 0-1;
m is 1-2;
A is selected from the group consisting of NR2, O, and S;
Axe2x80x2 is selected from the group consisting of NR3, O, S and CR4R5;
D is selected from the group consisting of CH2 and C(O);
Dxe2x80x2 is selected from the group consisting of CH2, C(O), S(O), and S(O)2;
R1 is selected from the group consisting of aryl and heterocycle;
R2 and R3 are independently selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NZ1Z2, and (NZ1Z2)alkyl wherein Z1 and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl;
R4 and R5 are independently selected from the group consisting of hydrogen and alkyl;
or
R4 and R5 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring;
R6 and R7 are independently selected from the group consisting of hydrogen and alkyl;
or
R6 and R7 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring; and
R8 and R9 are independently selected from the group consisting of hydrogen and alkyl;
or
R8 and R9 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring;
with the proviso that when D is CH2 then Dxe2x80x2 is other than CH2; and
with the proviso that when Dxe2x80x2 is S(O) or S(O)2 then Axe2x80x2 is CR4R5.
In another embodiment, the present invention discloses compounds having formula II: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein, A is NR2; and Axe2x80x2, Dxe2x80x2, R1, R2, R6, R7, R8, R9, m, and n are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein, A is O; and Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, Ra, m, and n are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein, A is S; and Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I.
In another embodiment, the present invention discloses compounds having formula III: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I with the proviso that Dxe2x80x2 is not CH2.
In another embodiment of the present invention, compounds have formula III wherein, A is NR2; and Axe2x80x2, Dxe2x80x2, R1, R2, R6, R7, R8, R9, m, and n are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein, A is O; and Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein, A is S; and Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I.
In another embodiment, the present invention discloses compounds having formula IV: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, Axe2x80x2, R1, R6, R7, R8, and R9, are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is NR2; Axe2x80x2 is NR3; and R1, R2, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is NR2; Axe2x80x2 is NR3; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1, R2, and R3 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is NR2; Axe2x80x2 is O; and R1, R2, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is NR2; Axe2x80x2 is S; and R1, R2, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is NR3; and R1, R3, R6, R7, R9, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is NR3; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R3 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is O; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is O; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is O; R6 is hydrogen; R7 is hydrogen; R8 is alkyl; R9 is selected from hydrogen and alkyl; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is O; R6 is alkyl; R7 is selected from hydrogen and alkyl; R8 is alkyl; R9 is selected from hydrogen and alkyl; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is S; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is O; Axe2x80x2 is S; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is S; Axe2x80x2 is NR3; and R1, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is S; Axe2x80x2 is O; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein, A is S; Axe2x80x2 is S; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment, the present invention discloses compounds having formula V: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, Axe2x80x2, R1, R6, R7, R8, and R9, are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is NR2; Axe2x80x2 is NR3; and R1, R2, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is NR2; Axe2x80x2 is O; and R1, R2, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is NR2; Axe2x80x2 is O; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R2 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is NR2; Axe2x80x2 is S; and R1, R2, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is NR2; Axe2x80x2 is CR4R5; and R1, R2, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is NR2; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R2 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is NR3; and R1, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is NR3; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R3 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is O; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is O; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is O; R6 is hydrogen; R7 is hydrogen; R8 is alkyl; R9 is selected from hydrogen and alkyl; and R1 is as defined in formula I.
n another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is O; R6 is alkyl; R7 is selected from hydrogen and alkyl; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is S; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is CR4R5; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is O; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is alkyl; R9 is selected from hydrogen and alkyl; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is S; Axe2x80x2 is NR3; and R1, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is S; Axe2x80x2 is O; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is S; Axe2x80x2 is S; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is S; Axe2x80x2 is CR4R5; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein, A is S; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment, the present invention discloses compounds having formula VI: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, Axe2x80x2, R1, R6, R7, R8, and R9, are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is NR2; Axe2x80x2 is NR3; and R1, R2, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is NR2; Axe2x80x2 is O; and R1, R2, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is NR2; Axe2x80x2 is S; and R1, R2, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is NR2; Axe2x80x2 is CR4R5; and R1, R2, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is NR2; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R2 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is NR3; and R1, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is NR3; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R3 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is O; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is S; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is CR4R5; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is CR4R5; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1, R4, and R5 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is O; Axe2x80x2 is CR4R5; R4 is methyl; R5 is methyl; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is S; Axe2x80x2 is NR3; and R1, R3, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is S; Axe2x80x2 is O; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is S; Axe2x80x2 is S; and R1, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is S; Axe2x80x2 is CR4R5; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein, A is S; Axe2x80x2 is CR4R5; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment, the present invention discloses compounds having formula VII: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, R1, R4, R5, R6, R7, R8, and R9, are as defined in formula I.
In another embodiment of the present invention, compounds have formula VII wherein, A is NR2; and R1, R2, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VII wherein, A is NR2; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R2 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VII wherein, A is O; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VII wherein, A is O; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula VII wherein, A is O; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is alkyl; R9 is selected from hydrogen and alkyl; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula VII wherein, A is S; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment, the present invention discloses compounds having formula VIII: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein, A, R1, R4, R5, R6, R7, R8, and R9, are as defined in formula I.
In another embodiment of the present invention, compounds have formula VIII wherein, A is NR2; and R1, R2, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VIII wherein, A is NR2; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 and R2 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VIII wherein, A is O; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VIII wherein, A is O; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; and R1 is as defined in formula I.
In another embodiment of the present invention, compounds have formula VIII wherein, A is S; and R1, R4, R5, R6, R7, R8, and R9 are as defined in formula I.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-VIII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating male sexual dysfunction including, but not limited, to male erectile dysfunction and premature ejaculation comprising administering a therapeutically effective amount of a compound of formula I-VIII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising administering a therapeutically effective amount of a compound of formula I-VIII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, Raynaud""s syndrome, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke comprising administering a therapeutically effective amount of a compound of formula I-VIII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
The present invention utilizes novel intermediates for making compounds of formula I. In particular, an intermediate of formula IX may be used in the process of synthesizing compounds of formula I, 
wherein A is selected from the group consisting of O, S, and NR2, wherein R2 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NZ1Z2, and (NZ1Z2)alkyl wherein Z1 and Z2 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl;
with the proviso that R2 is other than benzyl; and
R8 and R9 are independently selected from the group consisting of hydrogen and alkyl or R8 and R9 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbonxe2x80x94carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
The term xe2x80x9calkoxyalkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl, 2-(2-methoxyethoxy)ethyl, and the like.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.
The term xe2x80x9calkoxycarbonylalkyl,xe2x80x9d as used herein, refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 2-tert-butoxycarbonylethyl, and the like.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term xe2x80x9calkylcarbonylalkyl,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxopentyl, and the like.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited, methylsulfinyl, ethylsulfinyl, and the like.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl, ethylsulfonyl, and the like.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl, and the like.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbonxe2x80x94carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
The aryl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfo, sulfonate, xe2x80x94NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and arylalkyl).
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
The term xe2x80x9carylcarbonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl, naphthoyl, and the like.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.
The term xe2x80x9caryloxyalkyl,xe2x80x9d as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl, 3-bromophenoxymethyl, and the like.
The term xe2x80x9cazido,xe2x80x9d as used herein, refers to a xe2x80x94N3 group.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO)H group.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, and the like.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, 4-cycloheptylbutyl, and the like.
The term xe2x80x9cformyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to a monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.
The heterocycle groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfo, sulfonate, xe2x80x94NR80 R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and arylalkyl).
The term xe2x80x9cheterocyclealkyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein is a subset of alkyl and refers to a straight or branched chain hydrocarbon group containing from 1-to-4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cnitrogen protecting group,xe2x80x9d as used herein, refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures. N-protecting groups comprise carbamates, amides including those containing hetero arylgroups, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives and N-heteroatom derivatives. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is hereby incorporated by reference.
The term xe2x80x9cxe2x80x94NZ1Z2,xe2x80x9d as used herein, refers to two groups, Z1 and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl. Representative examples of xe2x80x94NZ1Z2 include, but are not limited to, amino, benzylamino, methylamino, acetylamino, acetylmethylamino, and the like.
The term xe2x80x9c(NZ1Z2)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NZ1Z2 group, as defined herein, appended to the parent molecula moiety through an alkyl group, as defined herein. Representative examples of (NZ1Z2)alkyl include, but are not limited to, aminomethyl, dimethylaminomethyl, 2(amino)ethyl, 2-(dimethylamino)ethyl, and the like.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a xe2x95x90O moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a xe2x80x94Oxe2x80x94 moiety.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfo,xe2x80x9d as used herein, refers to a xe2x80x94SO3H group.
The term xe2x80x9csulfonate,xe2x80x9d as used herein, refers to xe2x80x94S(O)2OR96 group, wherein R96 is selected from alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a xe2x80x94Sxe2x80x94 moiety.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in (T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987)).
The present invention contemplates pharmaceutically active metabolites formed by in vivo biotransformation of compounds of formula I-VIII. The term pharmaceutically active metabolite, as used herein, refers to a compound formed by the in vivo biotransformation of compounds of formula I-VIII. A thorough discussion of biotransformation is provided in Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, seventh edition.
Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Preferred compounds of formula I include, but are not limited to:
5-[3-(2-furyl)-4-methylphenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione,
5-[3-chloro-4-(trifluoromethyl)phenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione,
9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydro-1H-pyrrolo[3,4-b][1,7]naphthyridine-1,8(4H)-dione,
5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-thiopyrano[3,4-b][1,7]naphthyridine-4,6(3H,7H)-dione,
5-(3-bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-dithiopyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione,
9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H-furo[3,4-b]thiopyrano[4,3-e]pyridine-1,8(4H,7H)-dione,
9-(3-bromo-4-fluorophenyl)-2,3,5,9-tetrahydropyrrolo[3,4-b]thiopyrano[4,3-e]pyridine-1,8(4H,7H)-dione,
10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydropyrido[3,4-b][1,6]naphthyridine-1,9(2H,5H)-dione,
10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-1H-pyrano[4,3-b][1,7]naphthyridine-1,9(5H)-dione,
10-(3-bromo-4-fluorophenyl)-3,4,6,10-tetrahydrodipyrano[3,4-b:3,4-e]pyridine-1,9(5H,8H)-dione,
10-(3-bromo-4-fluorophenyl)-3,4,6,10-tetrahydro-2H-thiopyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione,
10-(3-bromo-4-fluorophenyl)-3,4,6,10-tetrahydropyrano[4,3-b]thiopyrano[4,3-e]pyridine-1,9(5H,8H)-dione,
5-(3-bromo-4-fluorophenyl)-7,7-dimethyl-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione,
9-(3-bromo-4-fluorophenyl)-2,3,5,9-tetrahydro-4H-thieno[3,2-b]thiopyrano[4,3-e]pyridin-8(7H)-one 1,1-dioxide,
10-(3-bromo-4-fluorophenyl)-3,4,6,10-tetrahydro-2H,5H-dithiopyrano[3,2-b:4,3-e]pyridin-9(8H)-one 1,1-dioxide, and
5-(3-bromo-4-fluorophenyl)-7,7-dimethyl-5,8,9,10-tetrahydro-1H-thiopyrano[3,4-b]quinoline-4,6(3H,7H)-dione or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
More preferred compounds of formula I include,but are not limited to:
5-(3-bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione;
5-(3-bromo-4-fluorophenyl)-2-methyl-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione;
5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydropyrido[3,4-b][1,7]naphthyridine-4,6(1H,7H)-dione;
(xe2x88x92)-5-(3-bromo-4-fluorophenyl)-2,3,5,7,8,9-hexahydro-1H-cyclopenta[b][1,7]naphthyridine-4,6-dione;
(+)-5-(3-bromo-4-fluorophenyl)-2,3,5,7,8,9-hexahydro-1H-cyclopenta[b][1,7]naphthyridine-4,6-dione;
(xe2x88x92)-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione;
(+)-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione;
10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b][1,7]naphthyridin-9(5H)-one 1,1-dioxide;
9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b][1,7]naphthyridin-8(4H)-one 1,1-dioxide;
9-(3-bromo-4-fluorophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(+)-9-(3-bromo-4-fluorophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(xe2x88x92)-9-(3-bromo-4-fluorophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
9-(3-cyanophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(+)9-(3-cyanophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(xe2x88x92)9-(3-cyanophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
9-(4-chloro-3-nitrophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(+)-9-(4-chloro-3-nitrophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(xe2x88x92)-9-(4-chloro-3-nitrophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-pyrano[3,4-b]quinoline-4,6(3H,7H)-dione;
10-(3-bromo-4-fluorophenyl)-3,4,6,10-tetrahydro-2H,5H-pyrano[3,4-b]thiopyrano[2,3-e]pyridin-9(8H)-one 1,1-dioxide;
5-(3-bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-pyrano[3,4-b]thiopyrano[4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-bromo-4-fluorophenyl)-5,7,8,9-tetrahydrocyclopenta[b]pyrano[4,3-e]pyridine-4,6(1H,3H)-dione;
5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-pyrano[3,4-b][1,7]naphthyridine-4,6(3H,7H)-dione;
9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3-bromo-4-fluorophenyl)-2-methyl-2,3,5,9-tetrahydropyrano[3,4-b]pyrrolo[3,4-e]pyridine-1,8(4H,7H)-dione;
9-(3-bromo-4-fluorophenyl)-2,3,5,9-tetrahydropyrano[3,4-b]pyrrolo[3,4-e]pyridine-1,8(4H,7H)-dione;
5-(4-chloro-3-nitrophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-cyanophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(4-fluoro-3-iodophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(5-bromo-2-hydroxyphenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-[4-fluoro-3-(trifluoromethyl)phenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3,4-dichlorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(2,1,3-benzoxadiazol-5-yl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(5-nitro-2-thienyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(5-nitro-3-thienyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
(+)9-(4-fluoro-3-iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(xe2x88x92)9-(4-fluoro-3-iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
(+)5-(3-chloro-4-fluorophenyl)-2,3,5,7,8,9-hexahydro-1H-cyclopenta[b][1,7]naphthyridine-4,6-dione;
(xe2x88x92)5-(3-chloro-4-fluorophenyl)-2,3,5,7,8,9-hexahydro-1H-cyclopenta[b][1,7]naphthyridine-4,6-dione;
9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydrofuro[3,4-b][1,7]naphthyridine-1,8(3H,4H)-dione;
(+)9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydrofuro[3,4-b][1,7]naphthyridine-1,8(3H,4H)-dione;
(xe2x88x92)9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydrofuro[3,4-b][1,7]naphthyridine-1,8(3H,4H)-dione;
5-(3-bromo-4-fluorophenyl)-7,7-dimethyl-5,8,9,10-tetrahydro-1H-pyrano[3,4-b]quinoline-4,6(3H,7H)-dione;
(9R)-9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(9S)-9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
10-(3-chloro-4-fluorophenyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
10-(3,4-dichlorophenyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
10-[4-chloro-3-(trifluoromethyl)phenyl]-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
10-(4-chloro-3-nitrophenyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
10-(3,4-dibromophenyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
10-(5-nitro-3-thienyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-thiopyrano[3,4-b]quinoline-4,6(3H,7H)-dione;
5-(3-bromo-4-fluorophenyl)-5,7,8,9-tetrahydrocyclopenta[b]thiopyrano[4,3-e]pyridine-4,6(1H,3H)-dione;
10-(3-bromo-4-fluorophenyl)-3,4,6,10-tetrahydro-2H-pyrano[3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione;
5-(3-bromo-4-methylphenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-iodo-4-methylphenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3,4-dibromophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-[4-chloro-3-(trifluoromethyl)phenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-[4-fluoro-3-(2-furyl)phenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(5-bromo-4-fluoro-2-hydroxyphenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(4-methyl-3-nitrophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(4-bromo-3-chlorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-bromo-4-chlorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-[3-iodo-4-(trifluoromethyl)phenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-[3-bromo-4-(trifluoromethyl)phenyl]-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(4-fluoro-3-isopropenylphenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(4-fluorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-bromo-4-fluorophenyl)-3,3,7,7-tetramethyl-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
5-(3-bromo-4-fluorophenyl)-3,3-dimethyl-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
9-(3-bromo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(4-fluoro-3-iodophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3,4-dibromophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3,4-dichlorophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-[4-chloro-3-(trifluoromethyl)phenyl]-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3-bromo-4-chlorophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(4-methyl-3-nitrophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-[3-(2-furyl)-4-methylphenyl]-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-[4-fluoro-3-(2-furyl)phenyl]-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(9S)-9-(4-fluoro-3-iodopheny)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyrdine-1,8(4H,7H)-dione;
(9R)-9-(4-fluoro-3-iodophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(9R)-9-(3-bromo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(9S)-9-(3-bromo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(+)9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(xe2x88x92)9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(trans)-9-(3-bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(cis)-9-(3-bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3-bromo-4-fluorophenyl)-7,7-dimethyl-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one 1,1-dioxide;
5-(3-bromo-4-fluorophenyl)-3,3-dimethyl-5,7,8,9-tetrahydrocyclopenta[b]pyrano[4,3-e]pyridine-4,6(1H,3H)-dione;
(trans)-9-(3-bromo-4-fluorophenyl)-5-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(cis)-9-(3-bromo-4-fluorophenyl)-5-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(trans)-9-(3-bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(cis)-9-(3-bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3-bromo-4-fluorophenyl)-7,7-dimethyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
spiro[5-(3-bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione-3,1xe2x80x2-cyclopentane];
5-(3-bromo-4-fluorophenyl)-3,3-diethyl-5,10-dihydro-1H,3H-dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione;
(cis)-9-(3-bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(trans)-9-(3-bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(cis)-9-(3-bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(trans)-9-(3-bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
9-(3-bromo-4-fluorophenyl)-3,3-dimethyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione;
(+)(cis)-9-(3-bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione; and
(xe2x88x92)(cis)-9-(3-bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione or a pharmaceutically acceptable salt, ester, amide,or prodrug thereof.
The following Schemes and Examples are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-58. Further,all citations herein are incorporated by reference. 
Dihydropyridines of general formula (4),wherein A,Axe2x80x2,D,Dxe2x80x2,R1, R6, R7, R8, R9, m and n are as defined in formula I, can be prepared as described in Scheme 1. Carbonyl compounds of general formula (1), aldehydes of general formula (2), and carbonyl compounds of general formula (3) can be combined in the presence of ammonia with heating in a solvent such as ethanol to provide dihydropyridines of general formula (4). 
Dicarbonyl compounds of general formula (9),wherein R8, R9, and A are as defined in formula I, can be prepared as described in Scheme 2. Esters of general formula (6), wherein A is selected from S or NR2 and wherein R2 is as defined in formula I, can be alkylated with chloroacetone to provide ketoesters of general formula (8). Ketoesters of general formula (8) can be cyclized in the presence of a base such as potassium tert-butoxide to provide dicarbonyl compounds of general formula (9). An alternative method of preparing ketoesters of general formula (8) can also be used. Acid chlorides of general formula (7), wherein A is O, prepared as described in (Terasawa, J. Org. Chem. (1977), 42, 1163-1169), can be treated with dimethyl zinc in the presence of a palladium catalyst to provide ketoesters of general formula (8).
An alternative method of preparing dicarbonyl compounds of general formula (9) can be used as described in Scheme 2. Alkynes of general formula (10) can be treated with methyl bromoacetate to provide ethers of general formula (11). A base such as sodium hydride may be necessary when A is O or S. Alkynes of general formula (11) can be treated with a catalyst such as mercuric acetate in the presence of a catalytic amount of sulfuric acid with heating in a solvent such as methanol followed by treatment with aqueous acid to provide methyl ketones of general formula (12). Methyl ketones of general formula (12) can be treated with a base such as potassium tert-butoxide to provide dicarbonyl compounds of general formula (9).
Alkynes of general formula (10), wherein A=O, can be purchased or prepared by reaction of a nucleophilic source of acetylene such a ethynylmagnesium bromide or lithium acetylide with an appropriate ketone or aldehyde.
Chiral alkynes of general formula (10), wherein A=O, can also be purchased or generated by known methods (Midland, M. Tetrahedron (1984), 40, 1371-1380; Smith, R. J.Med.Chem. (1988), 31, 1558-1566) and then processed to provide chiral dicarbonyl compounds of general formula (9).
Dicarbonyl compounds of general formula (9) may also be prepared using the procedures described in (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464; Terasawa, T., Journal of Organic Chemistry 42 (1977)1163); Fehnel, J.Amer.Chem.Soc., (1955), 77, 4241-4242; Morgan, J.Amer.Chem.Soc. (1957), 79, 422; and Er, Helv.Chim.Acta, (1992), 75, 2265-2269). 
Dicarbonyl compounds of general formula (13), wherein R6 and R7 are defined as in formula I and Axe2x80x2 is selected from O, S, and NR3 wherein R3 is selected from alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclealkyl, hydroxyalkyl, xe2x80x94NZ1Z2, and (NZ1Z2)alkyl wherein Z1 and Z2 are independently selected from the group consisting of alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, can be prepared as described in Scheme 3. Compounds of general formulas (6A), (7A) and (10A) can be processed as described in Scheme 2 to provide dicarbonyl compounds of general formula (13). 
Symmetrical dihydropyridines of formula (15), wherein A=Axe2x80x2, R6xe2x95x90R8, and R7xe2x95x90R9 and A, R1, R6, and R7 are as defined in formula I, can be prepared as described in Scheme 4. Two equivalents of dicarbonyl compounds of general formula (9) can be treated with aldehydes of general formula (2) and one equivalent of ammonia with heating in a solvent such as ethanol to provide symmetrical dihydropyridines of general formula (15). 
Dihydropyridines of general formula (15), wherein A, Axe2x80x2, R1 R6, R7, R8, and R9 are as defined in formula I, can be prepared as described in Scheme 5. One of the dicarbonyl components (9) or (13) can be treated with ammonia followed by addition of aldehydes of general formula (2) and the other dicarbonyl compound (9) or (13) with heating to provide dihydropyridines of general formula (15).
When R6 and R7 are not equivalent or R8 and R9 are not equivalent, a mixture of diastereomers results. These diastereomers, as well as diastereomers described in Schemes to follow, can be separated by methods know to those skilled to the art. 
Dihydropyridines of general formula (18), wherein A, Axe2x80x2, R1, R8, and R9 are as defined in formula I, can be prepared as described in Scheme 6. One of the dicarbonyl components (9) or (17) can be treated with ammonia followed by addition of aldehydes of general formula (2) and the other dicarbonyl compound (9) or (17) with heating to provide dihydropyridines of general formula (18). Dicarbonyl compounds of general formula (17) can be prepared as described in (d""Angelo, Tett. Lett. (1991), 32, 3063-3066; Nakagawa, Heterocycles (1979), 13, 477-495). 
Ketosulfones of general formula (23), wherein m is 1 or 2, can be prepared as described in Scheme 7. Reduction of ketone (20) with sodium borohydride (or the like) in a solvent such as ethanol provides alcohol (21) which can be oxidized to the corresponding sulfone (22) using an oxidizing agent such as hydrogen peroxide catalyzed by sodium tungstate. Oxidation of (22) using Jones"" reagent or the like provides the desired keto sulfone (23). 
Dihydropyridines of general formula (25), wherein A, m, R1, R8, and R9 are as defined in formula I, can be prepared as described in Scheme 8. Dicarbonyl compounds of general formula (9) can be treated with ammonia, followed by addition of (2) and ketosulfone (23) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (25). An additional heating step, with an acid such as HCl, may be required to drive the reaction to completion. 
An alternate method of preparing dihydropyridines of general formula (4), wherein A, Axe2x80x2, D, Dxe2x80x2, R1, R6, R7, R8, R9, m and n are as defined in formula I, can be used as described in Scheme 9. Enamines of general formula (27) can be treated with aldehydes (2) and carbonyl compounds (3) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (4). 
Enaminones of general formula (32) and (33), wherein A, R8, and R9 are as defined in formula I, can be prepared as described in Scheme 10. Dicarbonyl compounds (9) can be treated with an alcohol such as ethyl alcohol in the presence of an acid catalyst such as para-toluenesulfonic acid to provide vinyl ethers of general formula (30) and (31), wherein R is lower alkyl. Vinyl ethers of general formula (30) and (31) can be separated by a separatory method such as chromatography. Vinyl ethers of general formula (30) can be treated with ammonia in a solvent such as methanol to provide enaminones of general formula (32). Vinyl ethers of general formula (31) can be treated with ammonia in a solvent such as methanol to provide enaminones of general formula (33). 
A method of preparing dihydropyridines of general formula (15) and (35), wherein A, Axe2x80x2, R1, R6, R7, R8 and R9 are as defined in formula I, can be used as described in Scheme 11. Enaminones of general formula (32) can be treated with aldehydes of general formula (2) and dicarbonyls of general formula (13) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (15) and (35). 
A method of preparing dihydropyridines of general formula (37) and (38), wherein A, Axe2x80x2, R1, R6, R7, R8 and R9 are as defined in formula I, can be used as described in Scheme 12. Enaminones of general formula (33) can be treated with aldehydes (2) and dicarbonyls (13) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (37) and (38). 
Dihydropyridines of general formula (42), wherein A, R1, R8 and R9 and m are as defined in formula I, can be prepared as described in Scheme 13. Enaminones of general formula (32) can be treated with aldehydes (2) and dicarbonyl compounds of general formula (40) with heating in a solvent such as ethanol in the presence of a base such as triethylamine to provide a mixture of hemiaminals of general formula (41) and dihydropyridines of general formula (42). Hemiaminals (41) can be treated with heat in the presence of an acid such as HCl in a solvent such as ethanol to provide dihydropyridines of general formula (42). 
Dihydropyridines of general formula (44), wherein A, R1, R8 and R9 and m are as defined in formula I, can be prepared as described in Scheme 14. Enaminones of general formula (33) can be processed as described in Scheme 13 to provide dihydropyridines of general formula (44). 
An alternate method of preparing dihydropyridines of general formula (25), wherein A, R1, R8 and R9 and m are as defined in formula I, can be used as described in Scheme 15. Enaminones of general formula (32) can be treated with aldehydes (2) and ketosulfones (23) with heating in a solvent such as ethanol in the presence of a base such as triethylamine to provide hemiaminals of general formula (46) and dihydropyridines of general formula (25). Hemiaminals (46) can be treated with heat in the presence of an acid such as HCl in a solvent such as ethanol to provide dihydropyridines of general formula (25). 
A method of preparing dihydropyridines of general formula (48), wherein A, R1, R8 and R9 and m are as defined in formula I, can be used as described in Scheme 16. Enaminones of general formula (33) can be processed as described in Scheme 15 to provide dihydropyridines of general formula (48). 
An alternate method of preparing dihydropyridines of general formula (18), wherein A, Axe2x80x2, and R1, R8 and R9 are as defined in formula I, can be used as described in Scheme 17. Enaminones of general formula (32) can be treated with aldehydes (2) and dicarbonyls of general formula (17) with heating in a solvent such as ethanol in the presence of a base such as triethylamine to provide dihydropyridines of general formula (18). An additional heating step, with an acid such as HCl, may be required to drive the reaction to completion. 
A method of preparing dihydropyridines of general formula (50), wherein A, Axe2x80x2, and R1, R8 and R9 are as defined in formula I, can be used as described in Scheme 18. Enaminones of general formula (33) can be processed as described in Scheme 17 to provide dihydropyridines of general formula (50). 
Dihydropyridines of general formula (56) and (57), wherein A, R1, R3, R6, R7, R8, and R9 are as defined in formula I, can be prepared as described in Scheme 19. Enaminones of general formula (32) can be treated with aldehydes (2) and acetoacetates of general formula (52), wherein R is lower alkyl, to provide dihydropyridines of general formula (53). Dihydropyridines of general formula (53) can be treated with brominating agents such as N-bromosuccinimide or pyridinium tribromide in a solvent such as methanol, ethanol, isopropanol, or chloroform to provide dihydropyridines of general formula (54). Dihydropyridines of general formula (54) can be treated with primary amines of general formula (55) or ammonia with heat in a solvent such as ethanol to provide dihydropyridines of general formula (56). Dihydropyridines of general formula (54) can be heated neat or in a solvent such as chloroform to provide dihydropyridines of general formula (57). 
Dihydropyridines of general formula (59) and (60), wherein A, R1, R3, R6, R7, R8, R9 are as defined in formula I, can be prepared as described in Scheme 20. Enaminones of general formula (33) can be processed as described in Scheme 19 to provide dihydropyridines of general formula (59) and (60). 
An alternate method of preparing dihydropyridines of general formula (4), wherein A, Axe2x80x2, D, Dxe2x80x2, R1, R6, R7, R8, R9 m and n are as defined in formula I, can be used as described in Scheme 21. Carbonyl compounds of general formula (1) can be treated with aldehydes of general formula (2) and enamines of general formula (62) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (4). 
An alternate method of preparing dihydropyridines of general formula (42), wherein A, R1, R8, R9, and m are as defined in formula I, can be used as described in Scheme 22. Dicarbonyl compounds of general formula (9) can be treated with aldehydes (2) and aminocycloalkenones of general formula (63) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (42). An additional heating step, with an acid such as HCl, may be required to drive the reaction to completion. Aminocycloalkenones of general formula (63) can be purchased commercially such as 3-amino-2-cyclohexene-1-one (Fluka) or prepared as described in (Kikani, B. Synthesis, (1991), 2, 176). 
As shown in Scheme 23, enamines of general formula (66), wherein m is an integer from 1-2, can be prepared. Carbonyl compounds (23), from Scheme 7, can be converted to an intermediate enol ether of general formula (65) and thence to enamines of general formula (66). 
An alternate method of preparing dihydropyridines of general formula (25), wherein A, R1, R8, R9 and m are as defined in formula I, can be used as described in Scheme 24. Diones of general formula (9) can be treated with aldehydes of general formula (2) and aminosulfones of general formula (66) with heating in a solvent such as ethanol in the presence of a base such as triethylamine to provide hemiaminals of general formula (68) and dihydropyridines of general formula (25). The resulting mixture of hemiaminals (68) and dihydropyridines (25) can be heated with HCl in a solvent such as ethanol to provide dihydropyridines of general formula (25). 
An alternate method of preparing dihydropyridines of general formula (56) and (57), wherein A, R1, R3, R6, R7, R8, and R9 are as defined in formula I, can be used as described in Scheme 25. Diones of general formula (9) can be treated with aldehydes of general formula (2) and aminocrotonates of general formula (70), wherein R is lower alkyl, to provide dihydropyridines of general formula (53) which can be processed as described in Scheme 19 to provide dihydropyridines of general formula (56) and (57). Aminocrotonates of general formula (70) can be generated from reaction of acetoacetates of general formula (52) with ammonia. 
An alternate method of preparing dihydropyridines of general formula (4), wherein A, Axe2x80x2, D, Dxe2x80x2, R1, R6, R7, R8, R9, m and n are as defined in formula I, can be used as described in Scheme 26. Carbonyls of general formula (1) can be treated with xcex1,xcex2-unsaturated ketones of general formula (72) in the presence of ammonia with heating in a solvent such as ethanol to provide dihydropyridines of general formula (4). 
Dihydropyridines of general formula (77), wherein A, R1, R8, R9 and m are as defined in formula I, can be prepared as described in Scheme 27. xcex2-Keto sulfides (20) can be treated with secondary amines such as morpholine, pyrrolidine or piperidine to provide enamines (74) which can be condensed with aldehydes of general formula (2) in an appropriate organic solvent to provide sulfides of general formula (75). Sulfides of general formula (75) can be oxidized with an oxidant such as meta-chloroperoxybenzoic acid to sulfoxides of general formula (76). Sulfoxides of general formula (76) can be treated with dicarbonyls of general formula (9) and a source of ammonia such as ammonia, ammonium acetate or ammonium hydroxide with heating in a solvent such as ethyl alcohol or similar alcoholic solvent, acetonitrile or dimethylformamide to provide dihydropyridines of general formula (77). 
Dihydropyridines of general formula (81), wherein A, Axe2x80x2, R1, R8, R9 and m are as defined in formula I, can be prepared as described in Scheme 28. Carbonyl compounds of general formula (79) can be treated with aldehydes of general formula (2) using the Aldol reaction to provide ketones of general formula (80). The Aldol reaction and the conditions for this transformation are well known to those skilled in the art. Preferably, ketones of general formula (80) can be prepared by conversion of (79) to an enamine of morpholine, pyrrolidine or piperidine followed by direct reaction with aldehydes (2). Ketones of general formula (80) can be treated with diones of general formula (9) and ammonia to provide dihydropyridines of general formula (81). 
An alternate method of preparing dihydropyridines of general formula (4), wherein A, Axe2x80x2, D, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I, can be used as described in Scheme 29. Enamines of general formula (27) can be treated with xcex1, xcex2-unsaturated ketones of general formula (72) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (4). 
An alternate method for preparing dihydropyridines of general formula (77), wherein A, R1, R8, R9 and m are as defined in formula I, can be used as described in Scheme 30. Enaminones of general formula (32) can be treated with xcex1, xcex2-unsaturated sulfoxides (76) with heating in a solvent such as ethyl alcohol or similar alcoholic solvent, acetonitrile or dimethylformamide to provide dihydropyridines of general formula (77). 
A method for preparing dihydropyridines of general formula (83), wherein A, R1, R8, R9 and m are as defined in formula I, can be used as described in Scheme 31. Enaminones of general formula (33) can be processed as described in Scheme 30 to provide dihydropyridines of general formula (83). 
Dihydropyridines of general formula (87), wherein A, Axe2x80x2, R1, Dxe2x80x2, R6, R7, R8, R9, m, and n are as defined in formula I, can be prepared as described in Scheme 32. Carbonyls of general formula (85) can be treated with aldehydes of general formula (2) to provide xcex1, xcex2-unsaturated ketones of general formula (86) as described in (Eiden, F., Liebigs Ann.Chem., (1984), 11, 1759-1777). xcex1, xcex2-Unsaturated ketones of general formula (86) can be treated with carbonyls of general formula (3) in the presence of ammonia with heating in a solvent such as ethanol to provide dihydropyridiens of general formula (87). 
An alternate method of preparing dihydropyridines of general formula (87), wherein A, Axe2x80x2, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I, can be used as described in Scheme 33. xcex1, xcex2-Unsaturated ketones of general formula (86) can be treated with enamines of general formula (62) with heating in a solvent such as ethanol to provide dihydropyridines of general formula (87). 
An alternate method of preparing dihydropyridines of general formula (90), wherein A, Axe2x80x2, R1, R6, R7, R8, R9 and m are as defined in formula I, can be accomplished as described in Scheme 34. Dihydropyridines of general formula (89), from previous Schemes, can be reduced to provide dihydropyridines of general formula (90). Preferably, this transformation can be accomplished by conversion of (89) to the iminoether with trimethyl or triethyloxonium tetrafluoroborate and reduction with sodium borohydride. Alternatively, the carbonyl can be converted to the thiocarbonyl using Lawesson""s reagent. Desulfurization of the thiocarbonyl can be accomplished with Raney nickel under a hydrogen atmosphere. Desulfurization can also be accomplished by conversion to the sulfonium species via addition of an alkyl halide such iodomethane and then reduction with sodium borohydride. The carbonyl may also be reduced to the methylene under conditions described in (Lakhvich, F. A, et. al., J. Org. Chem. USSR (Eng. Transl.)25 (1989)1493-1498). 
A method of preparing dihydropyridines of general formula (93), wherein A, R1, R8, R9 and m are as described in formula I, can be used as described in Scheme 35. Dihydropyridines of general formula (92), prepared as described in previous Schemes can be processed as described in Scheme 34 to provide dihydropyridines of general formula (93). 
Dihydropyridines of general formula (98), wherein D, Dxe2x80x2, Axe2x80x2, R1, R2, R6, R7, R8, R9, m, and n are as defined in formula I, can be prepared as described in Scheme 36. Dihydropyridines of general formula (95) prepared as described in previous Schemes can be treated with vinyl chloroformate to provide dihydropyridines of general formula (96). Dihydropyridines of general formula (96) can be treated with an acid such as hydrochloric acid in a protic solvent such as water or methanol with heating to provide dihydropyridines of general formula (97). Dihydropyridines of general formula (97) can be alkylated using standard chemistry known to those skilled in the art to provide dihydropyridines of general formula (98). 
Dihydropyridines of general formula (103) and (104), wherein Axe2x80x2, D, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I, can be prepared as described in Scheme 37. Dihydropyridines of general formula (95), prepared as described in previous Schemes in particular Schemes 13 and 22, can be debenzylated as described in Scheme 36 and then treated with (8)-phenylmenthol chloroformate prepared from (xe2x88x92)8-phenylmenthol in a solvent such as tetrahydrofuran, methylene chloride, or chloroform or treated with (xe2x88x92)8-phenylmenthol chloroformate directly to produce a mixture of diastereomeric carbamates of general formula (101) and (102). The diastereomers (101) and (102) can be separated by column chromatography over silica gel and then treated with HBr in acetic acid to produce the enantiomeric dihydropyridines of general formula (103) and (104). 
Enantiomers of general formula (108) and (109), wherein A, Axe2x80x2, D, Dxe2x80x2, R1, R6, R7, R8, R9, m, and n are as defined in formula I, may be prepared as single enantiomers by the method illustrated in Scheme 38. Dihydropyridines of general formula (4) can be treated with a base such as potassium tert-butoxide in a solvent such as THF and the resulting anion can be reacted with the (xe2x88x92)-8-phenylmenthol chloroformate to produce a mixture of diastereomeric carbamates (106) and (107). These diastereomers can be separated by separatory methods known to those skilled in the art such as column chromatography over silica gel. The individual carbamates (106) and (107) can be treated with sodium methoxide in methanol to produce the single enantiomers (108) and (109) respectively. 
Enantiomers of general formula (111) and (112), wherein A, R1, R8, R9, and m are as defined in formula I, may be prepared as single enantiomers by the method illustrated in Scheme 39. Dihydropyridines of general formula (92) can be processed as described in Scheme 38 to provide the single enantiomers (111) and (112).
Many of the starting aryl and heteroaryl aldehydes necessary to carry out the methods described in the preceeding and following Schemes may be purchased from commercial sources or may be synthesized by known procedures found in the chemical literature. Appropriate literature references for the preparation of aryl and heteroaryl aldehydes may be found in the following section or in the Examples. For starting materials not previously described in the literature the following Schemes are intended to illustrate their preparation through a general method.
The preparation of aldehydes used to synthesize many preferred compounds of the invention may be found in the following literature references: Pearson, Org. Synth. Coll. Vol V (1973), 117; Nwaukwa, Tetrahedron Lett. (1982), 23, 3131; Badder, J. Indian Chem. Soc. (1976), 53, 1053; Khanna, J. Med. Chem. (1997), 40, 1634; Rinkes, Recl. Trav. Chim. Pays-Bas (1945), 64, 205; van der Lee, Recl. Trav. Chim. Pays-Bas (1926), 45, 687; Widman, Chem. Ber. (1882), 15, 167; Hodgson, J. Chem. Soc. (1927), 2425; Clark, J. Fluorine Chem. (1990), 50, 411; Hodgson, J. Chem. Soc. (1929), 1635; Duff, J. Chem. Soc. (1951), 1512; Crawford, J. Chem. Soc. (1956), 2155; Tanouchi, J. Med. Chem. (1981), 24, 1149; Bergmann, J. Am. Chem. Soc. (1959), 81, 5641; Other: Eistert, Chem. Ber. (1964), 97, 1470; Sekikawa, Bull. Chem. Soc. Jpn. (1959), 32, 551. 
Meta, para-disubstituted aldehydes of general formula (115), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be prepared according to the method described in Scheme 40. A para substituted aldehyde of general formula (114) or the corresponding acetal protected aldehyde of general formula (116), wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, may by subjected to conditions of an electrophilic aromatic substitution reaction to provide aldehydes of general formula (115) or protected aldehydes of general formula (117). Preferred protecting groups for compounds of general formula (116) and (117) include dimethyl or diethyl acetals or the 1,3-dioxolanes. These protecting groups can be introduced and removed using methods well known to those skilled in the art of organic chemistry. Removal of the protecting group of the compounds of general structure (117) provides substituted aldehydes of general formula (115). 
Aldehydes of general formula (121), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be prepared by the method described in Scheme 41. A meta substituted phenol (119) is converted to the para substituted salicylaldehyde (120) by reaction with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction. An alternate set of reaction conditions involves reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). The aldehyde (120) may be subjected to conditions of an electrophilic aromatic substitution reaction to provide meta, para disubstituted salicylaldehydes of general formula (121). 
An alternative method of preparing meta, para disubstituted salicylaldehydes of general formula (121), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be used as described in Scheme 42. A meta, para disubstituted phenol of general formula (123) can be reacted with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction, to provide disubstituted salicylaldehydes of general formula (121). An alternate set of reaction conditions involves reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). 
An alternative method of preparing benzaldehydes of general formula (115), wherein R12 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, alkylthio, nitro, alkylcarbonyl, arylcarbonyl, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, and formyl, is described in Scheme 43. Protected benzaldehydes of general formula (125), wherein Y is selected from bromine and iodine, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be converted to the 3,4-disubstituted protected benzaldehyde of general formula (117) via conversion to an intermediate lithio or magnesio derivative, followed by reaction with an appropriate electrophile such as an aldehyde, dialkyldisulfide, a Weinreb amide, dimethylformamide, an alkyl halide or the like. Deprotection of protected benzaldehydes of general structure (117) provide benzaldehydes of general formula (115).
An alternative method of preparing benzaldehydes of general formula (115), wherein R12 is selected from alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, alkynyl, vinyl, aryl, heteroaryl, cyano and the like, is also described in Scheme 43. Protected benzaldehydes of general formula (125), wherein Y is selected from bromine, iodine, and triflate, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be treated with an suitable tin, boronic acid, alkyne, or unsaturated halide reagent in the presence of a catalyst such as a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides protected benzaldehydes of general formula (117). Deprotection of the acetal of general formula (117) provides benzaldehydes of general formula (115).
An alternative method of preparing benzaldehydes of general formula (115), wherein R12 is selected from alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, alkynyl, vinyl, aryl, heteroaryl, cyano and the like, is also described in Scheme 43. Benzaldehydes of general formula (126) can be treated with a suitable tin, boronic acid, alkyne, or unsaturated halide reagent in the presence of a catalyst such as a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides aldehydes of general formula (115). 
An alternative method of preparing benzaldehydes of general formula (115), wherein R10 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R12 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, arylcarbonyl, and formyl, can be used as described in Scheme 44. Protected benzaldehydes of general formula (128), wherein Y is selected from bromine and iodine, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred can be converted to the 3,4-disubstituted protected benzaldehyde of general formula (117) via conversion to an intermediate lithio or magnesio derivative, followed by reaction with an appropriate electrophile such as an aldehyde, dialkyldisulfide, a Weinreb amide, dimethylformamide, an alkyl halide or the like. Deprotection of protected benzaldehydes of general structure (117) provide benzaldehydes of general formula (115).
An alternative method of preparing benzaldehydes of general formula (115), wherein R10 is selected from alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R12 is selected from alkyl, alkynyl, vinyl, aryl, heteroaryl, cyano and the like, is also described in Scheme 44. Protected benzaldehydes of general formula (128), wherein Y is selected from bromine, iodine, and triflate, and wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be treated with an suitable tin, boronic acid, alkyne, or unsaturated halide reagent in the presence of a catalyst such as a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides protected benzaldehydes of general formula (117). Deprotection of the acetal of general formula (117) provides benzaldehydes of general formula (115).
An alternative method of preparing benzaldehydes of general formula (115), wherein R10 is selected from alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R12 is selected from alkyl, alkynyl, vinyl, aryl, heteroaryl, cyano and the like, is also described in Scheme 44. Benzaldehydes of general formula (129) can be treated with a suitable tin, boronic acid, alkyne, or unsaturated halide reagent in the presence of a catalyst such as a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides aldehydes of general formula (115). 
Benzaldehydes of general formula (131), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from alkyl, arylalkyl, and haloalkyl wherein preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl and bromodifluoromethyl, can be prepared as described in Scheme 45. 3-Hydroxybenzaldehyde of general formula (130) can be treated with suitable alkylating reagents such as benzylbromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodifluoromethane, or dibromodifluoromethane in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide, to provide benzaldehydes of general formula (131). The synthesis of useful 3-hydroxybenzaldehydes of general formula (130) may be found in the following literature references: J. Chem. Soc. (1923), 2820; J. Med Chem. (1986), 29, 1982; Monatsh. Chem. (1963), 94, 1262; Justus Liebigs Ann. Chem. (1897), 294, 381; J. Chem. Soc. Perkin Trans. 1 (1990), 315; Tetrahedron Lett. (1990), 5495; J. Chem. Soc. Perkin Trans. 1 (1981), 2677. 
Benzaldehydes of general formula (133), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94NZ1Z2, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from alkyl, arylalkyl, and haloalkyl wherein preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl, and bromodifluoromethyl, can be prepared as described in Scheme 46. 4-Hydroxybenzaldehydes of general formula (132) can be treated with suitable alkylating reagents such as benzylbromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodifluoromethane, or dibromodifluoromethane, in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide to provide benzaldehydes of general formula (133). The synthesis of useful 4-hydroxybenzaldehydes of general formula (132) may be found in the following literature references: Angyal, J. Chem. Soc. (1950), 2141; Ginsburg, J. Am. Chem. Soc. (1951), 73, 702; Claisen, Justus Liebigs Ann. Chem. (1913), 401, 107; Nagao, Tetrahedron Lett. (1980), 21, 4931; Ferguson, J. Am. Chem. Soc. (1950), 72, 4324; Barnes, J. Chem. Soc. (1950), 2824; Villagomez-Ibarra, Tetrahedron (1995), 51, 9285; Komiyama, J. Am. Chem. Soc. (1983), 105, 2018; DE 87255; Hodgson, J. Chem. Soc. (1929), 469; Hodgson, J. Chem. Soc. (1929), 1641. 
An alternate method for introduction of substituents at the 3-position of benzaldehydes of general formula (115), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl can be used as described in Scheme 47. This method, also known as the Sandmeyer reaction, involves converting 3-amino benzaldehydes of general formula (135) to an intermediate diazonium salt with sodium nitrite. The diazonium salts can be treated with a bromine or iodine source to provide the bromide or iodide. The Sandmeyer reaction and conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde. The types of R12 substituents that may be introduced in this fashion include cyano, hydroxy, or halo. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde. The resulting iodide or bromide can then be treated with unsaturated halides, boronic acids or tin reagents in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) to provide benzaldehydes of general formula (115). The diazonium salts can also be treated directly with unsaturated halides, boronic acids or tin reagents in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) to provide benzaldehydes of general formula (115). 
An alternate method for introduction of substituents at the 4-position of benzaldehydes of general formula (115), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, can be used as described in Scheme 48. This method, also known as the Sandmeyer reaction, involves converting 4-amino benzaldehydes of general formula (136) to an intermediate diazonium salt with sodium nitrite and then treating the diazonium salts in a similar manner as that described in Scheme 47. The types of R10 substituents that may be introduced in this fashion include cyano, hydroxy, or halo. The Sandmeyer reaction and conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde. 
4-Bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde can be prepared as described in Scheme 49. The commercially available 4-bromo-2-(trifluoromethoxy)aniline can be protected on the amino group with a suitable N-protecting group well known to those skilled in the art of organic chemistry such as acetyl or tert-butoxycarbonyl. The bromine can then be converted to the lithio or magnesio derivative and reacted directly with dimethylformamide to provide the 4-aminoprotected-3-(trifluoromethoxy)benzaldehyde derivative. Removal of the N-protecting group followed by conversion of the amine to a bromide or chloride via the Sandmeyer method of Scheme 47 followed by hydrolysis of the dioxolane provides 4-bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde. 
4-Trifluoromethylbenzaldehydes of general formula (138), wherein X is selected from cyano, nitro, and halo may be prepared according to the method of Scheme 50. 4-Trifluoromethylbenzoic acid is first nitrated, using suitable conditions well known in the literature such as nitric acid with sulfric acid, and the carboxylic acid group reduced with borane to provide 3-nitro-4-trifluoromethylbenzyl alcohol. 3-Nitro-4-trifluoromethylbenzyl alcohol may be oxidized directly to 3-nitro-4-trifluoromethylbenzaldehyde by oxidation with typical reagents such as manganese dioxide. Alternatively, 3-nitro-4-trifluoromethylbenzyl alcohol can be reduced to the corresponding aniline using any of a number of different conditions for effecting this transformation among which a preferred method is hydrogenation over a palladium catalyst. The aniline can be converted to either a halo or cyano substituent using the Sandmeyer reaction described in Scheme 47 providing benzyl alcohols of general structure (137). Benzyl alcohols of general formula (137) can be oxidized using conditions well known to those skilled in the art such as manganese dioxide or Swern conditions to provide benzaldehydes of general formula (138).
For certain aromatic ring substitutions of R1 for compounds of the present invention it is preferable to effect transformations of the aromatic ring substitutions after the aldehyde has been incorporated into the core structure of the present invention. As such, compounds of the present invention may be further transformed to other distinct compounds of the present invention. These transformations involve Stille, Suzuki and Heck coupling reactions all of which are well known to those skilled in the art of organic chemistry. Shown below are some representative methods of such transformations of compounds of the present invention to other compounds of the present invention. 
Dihydropyridines of general formula (141), wherein A, Axe2x80x2, D, Dxe2x80x2, R6, R7, R8, R9, n and m are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R12 is selected from alkyl, vinyl, aryl, heteroaryl, cyano and the like, can be prepared as described in Scheme 51. Compounds of general formula (140), wherein X is selected from bromine, iodine, and triflate, are protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (141). The conditions for this transformation also effect the removal of the Boc protecting group. 
Dihydropyridines of general formula (144), wherein A, Axe2x80x2, D, Dxe2x80x2, R6, R7, R8, R9, m, and n are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R12 is selected from alkyl, vinyl, aryl, heteroaryl, cyano and the like, can be prepared as described in Scheme 52. Dihydropyridines of general formula (143), wherein X is selected from bromine, iodine, and triflate, can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be reacted with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (144). The conditions for this transformation also effect the removal of the Boc protecting group. 
Dihydropyridines of general formula (147), wherein A, Axe2x80x2, D, Dxe2x80x2, R6, R7, R8, R9, m, and n are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 53. Dihydropyridines of general formula (140), wherein X is selected from bromine, iodine, and triflate can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (147). The conditions for this transformation also effect the removal of the Boc protecting group. The types of meta substituents that may be introduced in this fashion include trihalopropenyl and more specifically the trifluoropropenyl group. 
Dihydropyridines of general formula (150), wherein A, Axe2x80x2, D, Dxe2x80x2, R6, R7, R8, R9, m and n are as defined in formula I, R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94C(O)NZ1Z2, wherein Z1 and Z2 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 54. Dihydropyridines of general formula (143), wherein X is selected from bromine, iodine, and triflate can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (150). The conditions for this transformation also effect the removal of the Boc protecting group. The types of para substituents that may be introduced in this fashion include trihalopropenyl and more specifically the trifluoropropenyl group. 
Dicarbonyl pyrans of general formula (165), wherein R8 and R9 are as defined in formula I, can be prepared as described in Scheme 55. (Trimethylsilyl)acetylene can be deprotonated with a base such as n-butyllithium, methyllithium or ethyl magnesium bromide in a solvent such as diethyl ether or tetrahydrofuran and then treated with an aldehyde of general formula (160) to provide propargyl alcohols of general formula (161). Propargyl alcohols of general formula (161) can be treated with a base such as sodium hydride and then treated with methyl bromoacetate in a solvent such as tetrahydrofuran to provide alkynes of general formula (162). Alkynes of general formula (162) can be treated with a base such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide and then treated with an alkylating agent such as an alkyl halide, alkyl triflate or the like in a solvent such as tetrahydrofuran to provide alkynes of general formula (163). Alkynes of general formula (163) can be treated with a source of mercury(II) such as mercury(II) acetate in the presence of acid in a solvent such as methanol followed by treatment with aqueous acid to provide methyl ketones of general formula (164). Methyl ketones of general formula (164) can be treated with a base such as potassium tert-butoxide to provide dicarbonyl pyrans of general formula (165). Dicarbonyl pyrans of general formula (165) can be processed as described in previous schemes to provide compounds of the present invention.
Propargyl alcohols of general formula (161) can be separated into single enantiomers as described in (Burgess, J. Amer. Chem. Soc. (1990), 112, 7434-7435; Burgess, J. Amer. Chem. Soc. (1991), 113, 6129-6139; Takano, Synthesis (1993), 12, 1253-1256; and Allevi, Tetrahedron Assymmetry (1997), 8, 93-100). Single enantiomers of general formula (161) can be processed as described in Scheme 55 to provide enantiomerically pure dicarbonyl pyrans of general formula (165). 
Dicarbonyl piperidines of general structure (173), wherein R8 and R9 are as defined in formula I, can be prepared as described in Scheme 56. Propargyl alcohols of general formula (161) from Scheme 55 can be converted to amines of general formula (170) under Mitsunobu conditions directly using ammonia or indirectly through an azide or a phthalimide intermediate as described in (Holmes, J. Chem. Soc. Perkin Trans. 1, (1991), 12, 3301-3306; Tabor, J. Chem. Soc., Chem. Comm. (1989), 15, 1025-1027; Cossy, Bioorg. Med. Chem. Lett. (1997), 7, 1699-1700; Mukai, Tett. Lett. (1991), 32, 7553-7556; and Mukai, J. Chem. Soc., Perkin Trans. 1, (1993), 5, 563-572). Amines of general formula (170) can be treated with methyl bromoacetate to provide aminoesters of general formula (171). Aminoesters of general formula (171) can be benzylated using a benzylating agent such as benzyl beomide in the presence of a base such as triethylamine to provide esters of general formula (172). Esters of general formula (172) can be processed as described in Scheme 55 to provide dicarbonyl compounds of general formula (173). Dicarbonyl piperidines of general structure (173) can be used as described in previous Schemes to provide compounds of the present invention.
An alternate method of preparing dicarbonyl compounds of general structure (173) can be used as described in Scheme 56. Propargy alcohols of general formula (161) from Scheme 55 can be treated with methanesulfonyl chloride or the like to provide an intermediate sulfonate which can be further treated with a N-benzyl protected amino acid ester of general formula (174) to provide esters of genral formula (175) as described in (Olsson, Acta Chem. Scand. Ser. B (1979), 33, 679-684; Geri, Gazz. Chim. Ital. (1994), 124, 241-248; Imada, J. Org. Chem, (1983), 26, 1036-1042; Sahlberg, J. Med. Chem. (1983), 26, 1036-1042; Bates, Tetrahedron (1995), 51, 12939-12954). Many N-benzyl protected amino acid ester of general formula (174) are known in the literature and can be synthesized enantiomerically pure. Esters of genral formula (175) can be processed as described in Scheme 55 to provide dicarbonyl compounds of general structure (173).
Chiral dicarbonyl piperidines of general structure (173) can be prepared as described in Scheme 56. Enantiomerically pure propargyl alcohols of general formula (161) can be processed to provide enantiomerically pure dicarbonyl piperidines of general structure (173). Enantiomericaaly pure N-benzyl protected amino acid ester of general formula (174) can be processed to provide enantiomerically pure dicarbonyl piperidines of general structure (173). 
Dicarbonyl thiopyrans of general structure (181), wherein R8 and R9 are as defined in formula I, can be prepared as described in Scheme 57. Propargyl alcohols of general formula (161) from Scheme 55 can be converted to the corresponding chlorides using chlorinating agents well known to those of skill in the art such as phosphorous oxychloride and then treated with a source of sulfur such as sodium hydrogen sulfide to provide thiols of general formula (180) as described in (Komasov, Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Trans.) (1963), 81-85). Thiols of general structure (180) can be processed as described in Scheme 55 to provide dicarbonyl thiopyrans of general structure (181). Dicarbonyl thiopyrans of general structure (181) can be processed as described in previous Schemes to provide compounds of the present invention.
Alternatively, dicarbonyl compounds of general formula (181) may be prepared using procedures as described in (Bergel, Nature(London) (1945), 155, 481). 
Enaminones of general formula (184) and (185) can be prepared as described in Scheme 58. Dicarbonyl compounds of general structure (183) can be processed as described in Scheme 10 to provide enaminones of general formula (184) and (185). Enaminones of general formula (184) and (185) can be processed as described in the previous Schemes to provide compounds of the present invention.
In addition to the use of the methods illustrated in Schemes 37 and 38, individual enantiomers of compounds of the present invention may also be separated by chiral chromatography.